Data from: PCNT point mutations and familial intracranial aneurysms

Objective: To identify novel genes involved in the etiology of
intracranial aneurysms (IA) and / or subarachnoid hemorrhages (SAH) using
whole exome sequencing. Methods. In the present study we performed whole
exome sequencing in thirteen individuals from three families with an
autosomal dominant IA/SAH inheritance pattern to look for candidate genes
for disease. Additionally, we sequenced PCNT exon 38 in 161 sporadic
IA/SAH patients in order to find additional carriers of potential
pathogenic variants. Results. We identified two different variants in exon
38 from the PCNT gene shared between affected members from two different
families with either IA or SAH (p.V2811L and p.R2728C). One hundred and
sixty four samples with either SAH or IA were Sanger sequenced for the
PCNT exon 38. Seven missense mutations were identified. We also found a
second p.V2811L carrier in a family with a history of neurovascular
diseases. Conclusions. The PCNT gene encodes a protein that is involved in
the process of microtubule nucleation and organization in interphase and
mitosis. Biallelic loss-of-function mutations in PCNT cause a form of
primordial dwarfism (MOPD-II) and ~50% of these patients will develop
neurovascular abnormalities, including IAs and SAH. Additionally, a
complete Pcnt knock-out mouse model (PcntM-/-) published previously showed
general vascular abnormalities, including intracranial hemorrhage. The
variants in our families lie in the highly conserved PCNT protein-protein
interaction domain, making PCNT a highly plausible candidate gene in
cerebrovascular disease.